Toxicokinetic modeling of folpet fungicide and its ring-biomarkers of exposure in humans

• Published in: Journal of applied toxicology 2013-07, Vol.33 (7), p.607-617
• Main Authors: Heredia-Ortiz, Roberto, Berthet, Aurélie, Bouchard, Michèle
• Format: Article
• Language: English
• Subjects: Administration, Oral; Administration, Topical; Algorithms; Area Under Curve; Biomarkers; Biomarkers - analysis; Biotransformation; Blood; folpet; Fungicides; Fungicides, Industrial - pharmacokinetics; Fungicides, Industrial - toxicity; Half-Life; Human; Humans; Inhalation Exposure; Kinetics; Mathematical models; Models, Biological; Models, Statistical; Pesticides; Pharmacokinetics; Phthalimides; Phthalimides - pharmacokinetics; Phthalimides - toxicity; Polyimide resins; toxicokinetics; Toxicology; Urine
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.1782

ABSTRACT A human in vivo toxicokinetic model was built to allow a better understanding of the toxicokinetics of folpet fungicide and its key ring biomarkers of exposure: phthalimide (PI), phthalamic acid (PAA) and phthalic acid (PA). Both PI and the sum of ring metabolites, expressed as PA equivalents (PAeq), may be used as biomarkers of exposure. The conceptual representation of the model was based on the analysis of the time course of these biomarkers in volunteers orally and dermally exposed to folpet. In the model, compartments were also used to represent the body burden of folpet and experimentally relevant PI, PAA and PA ring metabolites in blood and in key tissues as well as in excreta, hence urinary and feces. The time evolution of these biomarkers in each compartment of the model was then mathematically described by a system of coupled differential equations. The mathematical parameters of the model were then determined from best fits to the time courses of PI and PAeq in blood and urine of five volunteers administered orally 1 mg kg−1 and dermally 10 mg kg−1 of folpet. In the case of oral administration, the mean elimination half‐life of PI from blood (through feces, urine or metabolism) was found to be 39.9 h as compared with 28.0 h for PAeq. In the case of a dermal application, mean elimination half‐life of PI and PAeq was estimated to be 34.3 and 29.3 h, respectively. The average final fractions of administered dose recovered in urine as PI over the 0–96 h period were 0.030 and 0.002%, for oral and dermal exposure, respectively. Corresponding values for PAeq were 24.5 and 1.83%, respectively. Finally, the average clearance rate of PI from blood calculated from the oral and dermal data was 0.09 ± 0.03 and 0.13 ± 0.05 ml h−1 while the volume of distribution was 4.30 ± 1.12 and 6.05 ± 2.22 l, respectively. It was not possible to obtain the corresponding values from PAeq data owing to the lack of blood time course data. Copyright © 2011 John Wiley & Sons, Ltd. A human in vivo toxicokinetic model was built to allow a better understanding of the toxicokinetics of folpet fungicide and its key biomarkers of exposure, and to simulate the transformation of folpet into phthalimide and other ring‐metabolites: phthalamic and phthalic acids. The model closely reproduced the time courses of phthalimide in blood and urine as well as total ring‐metabolites in urine of five volunteers administered orally 1 mg kg−1 and dermally 10 mg kg−1 of folpet.